Sweat is an aqueous solution that is secreted onto the surface of the skin to aid in cooling off the body. And it also serves other functions, including protecting against infection. One of the components that is secreted in sweat is the protein, dermcidi. Dermcidin is an antimicrobial peptide that helps to fight off pathogenic bacteria or fungus that are present on the skin. Dermcidin is found predominantly in the pores of the human skin and it is transported through human sweat onto the epidermal surface of the skin. Upon detection of bacteria on the surface of the skin, dermcidin assembles itself through the aid of zinc(+2) ions into a pore formation. Following insertion into the bacterial membrane, the assembled structure transports ions through its pore and into the bacterial cell. The transported ions can then inhibit DNA, RNA, and protein synthesis, along with several other necessary functions in the bacterial cell. These destructive effects from the transported ions effectively kill the potentially harmful bacteria. Antimicrobial peptides, or AMP’s, take advantage of the difference in overall charge between human cell membranes and bacterial membranes. Human cell membranes contain more neutral lipids contributing to a more neutral membrane. And bacterial membranes contain more negatively charged phospholipids, which attribute to a net negative charge. Due to the more negative charge of bacterial membranes, most antimicrobial peptides are positively charged, allowing them to target bacteria specifically. Interestingly, dermcidin is not a cationic AMP (CAMP), but it is an anioinic AMP (AAMP) containing an overall negative charge. Coordinating zinc(+2) metal ions, which are abundant in sweat, help to increase dermcin’s charge (more positive), allowing dermcidin to effectively target the (negative) bacterial membrane. Dermcidin can be found in two structural confirmations depending on its environment. The first structural conformation occurs when dermcidin is in the skin pore and not in contact with any bacterial membrane. It is in an unassembled monomeric helix formation known as the helix-hinge-helix motif. When dermcidin is secreted onto the surface of the skin and comes into contact withbacterial membranes, it assembles into its second structural conformation. The trimerization of antiparallel peptide dimers forms a hexameric bundle. This hexameric bundle of oligomers is stabilized by zinc(+2) ions. And its formation results in an enclosed channel structure. Zinc(+2) ions between the two neighboring helices of the dimerized peptides stabilizes demcidin’s pore structure. The zinc ions are coordinated by the residues glutamate, aspartate, and histidine. The assembled dermcidin pore allows ions to travel through the hydrophobic bacterial membrane and into the cell. The hydrophobic outside surface shown in red allows the insertion of dermcidin into the likewise hydrophobic bacterial membrane. The hydrophilic interior, shown in blue, is necessary to allow charged ions to travel into the bacterial cell. Interestingly, the ions flowing through the demcidin channel do not travel in a straight path from the outer portion of the membrane to the inside of the bacterial cell. Hydrophobic residues block the entrance of ions directly through the pore termini. Because of this capping of the channel that occurs, the transported ions need to utilize an alternative method of entry and exit through the channels sides near the termini. So why use zinc selected for the metal complex of dermcidin? The metal center of dermcidin, which is zinc, has an oxidation state of +2. The coordinated ligands, glutamate and aspartate, are each negatively charged at physiological pH, Giving a -3 charge for the complex before coordinating with zinc(+2). When zinc(+2) is coordinated the overall charge of the coordination complex is decreased to negative 1. The positive charge on the zinc helps the overall charge of the coordination complex become less negative, which is beneficial as dermcidin can more effectively target the negatively charged bacterial membranes. The +2 oxidation state of zinc gives zinc 2 plus a d- electron count of 10. With each ligand donating 2 electrons to zinc(+2) and 10 electrons contributed from the D orbital the total electron count for this system is 18, Indicating that zinc 2 plus is coordinately saturated and thus in a stable conformation. Due to the coordinated zinc(+2)metal ions full d-orbital its ligand field stabilization energy is zero: a consequence of which is a lack of preference toward a particular geometry. Since zinc(+2) is coordinately saturated with four ligands, the choice in geometry narrows down to either tetrahedral or square planar. By looking at the steric constraints, the more favorable geometry is tetrahedral, as the bond angles between neighboring ligands are greatest. Geometric constraints are an additional factor that could be determining the geometry due to the placement of the for coordinating ligands on their respective alpha helices. the four donor groups that zinc(+2) is coordinated to, two of the donor groups come from one alpha helix, and the other two donor groups come from an adjacent anti-parallel alpha helix. Each of these helices is acting as a bidentate ligand, possessing two donor groups to which the zinc binds. It can be assumed that the zinc(+2) is attached to water molecules prior to binding to the ligand donor groups. Thus, when the metal complex is formed the entropic penalty is decreased because each helix acts as a chelator, which increases the affinity of dermcidin for zinc(+2)? According to hard-soft acid-base theory, zinc is classified as a borderline acid and the histidine imidazole is classified as a borderline base. While both aspartate and glutamate are classified as hard bases. Due to the mixed hard-soft character of the ligands the selectivity of a borderline metal such as zinc is necessary. As stated previously, Zinc(+2) has an LFSE of 0. This means the metal complex would be thermodynamically unstable and consequently, kinetically labile. However, the zinc(+2) metal ion’s charge allows strong electrostatic attraction with the negatively charged ligands, resulting in the metal complex having more inert qualities compared to zinc(+2) coordinated to neutral ligands. The overall inert nature of the metal complex allows the dermcidin channel to remain structurally stable while it performs its antimicrobial function. Zinc two-plus plays a key role in ensuring dermcidin’s functionality, without which humans would have increased bacterial and fungal infection on the skin. So, if you’d like to experience dermcidin’s antimicrobial function today, I recommend you sweat!